In my research on the clinical pharmacology of the coumarin anticoagulant drugs, I continue to explore the quantitative determinants of drug action in man. The oral anticoagulants may be the best drug system known for precisely evaluating pharmacodynamic effects in man and correlating them with pharmacokinetic changes of the drug itself. Recent breakthroughs that will greatly enhance my study of the metabolism of the oral anticoagulants in man are: (1) a more sensitive assay for warfarin and its metabolites with a spectrofluorometric assay, (2) a more specific assay for unchanged warfarin by means of separation with thin-layer chromatography, (3) fractionation of plasma warfarin into free and bound components by ultrafiltration, (4) the availability of the resolved optical enantiomorphs of racemic warfarin for clinical studes and (5) of the high-molecular-weight tissue forms of menaquinone (vitamin K2) for animal studies. These modalities will be used in the examination of: (A) known drug interactions with oral anticoagulants (phenylbutazone and barbiturates), (B) known disease interactions (hepatic insufficiency, renal disease, and hereditary resistance to oral anticoagulants), and (C) newly discovered drug interactions (disulfiram and rifampin). Studying the pharmacodynamics of each optical enantiomorph of sodium warfarin will allow us to evaluate the relative contribution of each to anticoagulant action and to drug interactions. Drug therapy in general and anticoagulant therapy in particular will be made safer by understanding the sources of variation and the mechanisms of action and interaction. Oral anticoagulants are a model system for probing problems in clinical pharmacology.